Nanoparticle‐Mediated Inhibition of Acute Leukemic Stem Cells

Abstract

Chemoresistance accounts for 90% of failed chemotherapeutic treatments. Chemoresistant cancer stem cells (CSC) contribute to these poor outcomes via self‐renewal and non‐tumorigenic differentiation. While CSC subpopulations have been shown to contribute to cancer advancement and recurrence, targeting them has proven difficult. Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat many types of solid and hematologic cancers, including leukemia. Leukemic stem cells (LSC) are associated with chemoresistance, tumor relapse, and poor patient survival. DOX exhibits broad cytotoxicity but is accompanied by severe and sometimes life‐threatening toxicities. We have developed DOX‐loaded polymeric nanoparticles (DOX‐NP) to overcome these problems. These novel, patented nanoparticle delivery systems can diminish adverse effects of DOX administration, such as cardiac toxicity, via improved biodistribution and preferential accumulation in cancer sites. Nanoparticle‐mediated delivery of DOX shows promise as a potential treatment to specifically target LSC. Previous findings from a collaborative effort revealed the ability of low‐dose DOX to specifically inhibit pS552‐β‐catenin, a key mediator of LSC self‐renewal in T‐cell acute lymphocytic leukemia (T‐ALL). Our DOX‐NPs exhibited long circulation times and improved cardiac toxicity compared to free DOX. In vivo, our DOX‐NPs successfully inhibited LSC and promoted normal HSPC recovery with 3‐fold greater median survival than Doxil® (FDA‐approved liposomal DOX) in a patient‐derived xenograft (PDX) model of T‐ALL. In contrast, Doxil® promoted LSC expansion. To identify the mechanisms underlying the DOX‐NP treatment advantages, DOX‐NPs were compared with Doxil® based on in vitro DOX release, cytotoxicity to leukemic cells and bone marrow cells, and in vivo bone marrow accumulation. The DOX‐NPs exhibited slower drug release than Doxil®, which may allow for longer exposure of DOX to LSC. Significant bone marrow accumulation has been observed in both nanoparticle systems. Further understanding of the contribution of DOX accumulation in bone marrow to LSC inhibition in addition to determining the cytotoxicity of both DOX formulations to LSC and leukemic cells will aid in designing an effective drug‐loaded nanotherapeutic to target pS552‐β‐catenin for inhibiting LSC self‐renewal.Support or Funding InformationThis work was supported by the UCONN Academic Plan Grant, the Promising Project Award from the Program in Innovation Therapeutics for Connecticut's Health (PITCH), and the UCONN START PPOC grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.